HCMV protein kinase and DNA polymerase domains involved in antiviral sensitivity, viral replication and cell tropism

许多免疫系统受损的个体，如艾滋病毒/艾滋病患者、癌症患者和移植受者，都有感染人类巨细胞病毒（HCMV）的风险。目前，最有效的治疗方法是通过持续给予抗病毒剂来抑制病毒复制，主要是更昔洛韦（GCV）、西多福韦（CDV）或膦甲酸（膦甲酸或PFA）。在越来越多的不可逆慢性免疫抑制患者中使用抗病毒药物的持续时间越来越长，导致这组个体中出现越来越多的耐药HCMV病毒。在艾滋病患者中，一项研究中7.6%的分离株被证明是GCV耐药的，我们在免疫抑制的澳大利亚人中发现了类似的水平（10.8%）。在少数对HCMV具有任何有用活性的抗病毒剂中，GCV和阿昔洛韦（ACV）是核苷类似物。PFA是一种焦磷酸类似物，竞争性抑制HCMV DNA聚合酶与焦磷酸的结合。这些药物由HCMV的特定基因（UL 97（Pk））和与HCMV非常相似的小鼠病毒（MCMV-M97 Pk）激活。然后，药物作用于编码DNA聚合酶（HCMV UL 54 DP或MCMV M54 DP）的第二个基因，以防止病毒生长。我们正在调查CMV对包括GCV、CDV和PFA在内的7种抗病毒药物耐药的耐药基因型和表型。我们已经展示了新的耐药基因型，目前正在确定基因型变化的蛋白质功能相关性，以增加对PK和DP基因的理解，确定耐药的遗传原因，并产生更好的抗病毒药物靶点。

Many individuals with compromised immune systems - such as those with HIV-AIDS, cancer and transplant recipients are at risk of disease from human cytomegalovirus (HCMV) infection. Currently the most effective therapies are suppression of virus replication by continuing administration of antiviral agents, principally ganciclovir (GCV), cidofovir (CDV) or foscarnet (phosphonoformic acid or PFA). The use of antivirals for increasingly longer durations in an enlarging population of patients with irreversible chronic immunosuppression, has resulted in the emergence of increasing numbers of drug-resistant HCMV viruses in this group of individuals. In patients with AIDS, 7.6% of isolates in one study were shown to be GCV resistant and we have found similar levels (10.8%) in immunosuppressed Australians. Of the small number of antiviral agents with any useful activity against HCMV, GCV, and aciclovir (ACV) are nucleoside analogues. PFA is a pyrophosphate analogue that competitively inhibits pyrophosphate binding by HCMV DNA polymerase. These drugs are activated by a specific gene of HCMV (UL97 (Pk)) and a mouse virus (MCMV - M97Pk) that is very similar to HCMV. The drug then acts on a second gene encoding the DNA polymerase (HCMV UL54 DP or MCMV M54DP) to prevent viral growth. We are investigating the resistance genotypes and phenotypes in CMV resistant to 7 antiviral drugs including GCV, CDV and PFA. We have shown new resistant genotypes and are currently determining the protein-functional correlates of the genotypic changes, in order to increase understanding of the PK and DP genes, define the genetic causes of resistance, and to produce better targets for antiviral agents.